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Background Glioblastoma multiforme (GBM), the most common brain malignancy in adults, is generally aggressive and incurable, even with multiple treatment modalities and agents. Filamins (FLNs) are a group of actin-binding proteins that regulate the actin cytoskeleton in cells. However, the role of FLNs in malignancies—particularly in GBM—is unclear. Methods The relation between FLNC expression and overall survival in GBM was evaluated by the Kaplan−Meier analysis using GBM patients from the Kagoshima University Hospital ( n  = 90) and data from the Cancer Genome Atlas (TCGA) ( n  = 153). To assess FLNC function in GBM, cell migration and invasion were examined with Transwell and Matrigel invasion assays using FLNC-overexpressing U251MG and LN299 GBM cells, and ShRNA-mediated FLNC knocked-down KNS81 and U87MG cells. The gelatin zymography assay was used to estimate matrix metalloproteinase (MMP) 2 activity. Results In silico analysis of GBM patient data from TCGA and immunohistochemical analyses of clinical GBM specimens revealed that increased FLNC expression was associated with poor patient prognosis. FLNC overexpression in GBM cell lines was positively correlated with enhanced invasiveness, but not migration, and was accompanied by upregulation of MMP2. Conclusions FLNC is a potential therapeutic target and biomarker for GBM progression.

PurposeDiabetes insipidus (DI) following transsphenoidal surgery (TSS) is a common complication. Although postoperative DI often occurs in patients with craniopharyngioma and Rathke’s cleft cyst, postoperative DI in patients with non-functioning pituitary adenoma (NFPA) has not been fully examined. We clarified the clinical characteristics and magnetic resonance imaging (MRI) findings predicting postoperative DI in NFPAs.MethodsA total of 333 patients undergoing initial TSS for NFPA were included in this retrospective study. Hyperintensity (HI) in the posterior pituitary lobe was evaluated on preoperative T1-weighted MRI. Based on the findings of HI patients were divided into three groups as follows: HI was not detected (Disappearance group), HI located intrasellarly (Intrasellar group), and HI located suprasellarly (Suprasellar group).ResultsThe overall rate of DI was 21.9%, including permanent DI in 0.6%. DI occurred at postoperative day 1 (72.6%) or day 2 (19.2%) and improved within 7 days in most cases (87.7%). Univariable and multivariable analyses showed that the predictive factors of DI were a younger age (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.95–0.99, P = 0.0037) and larger tumor diameter (OR 1.04, 95% CI 1.01–1.08, P = 0.0155). The rate of DI was highest in the Disappearance group (43.8%) followed by the Intrasellar group (26.0%). The OR was 2.17 in the Intrasellar group compared with the Suprasellar group (95% CI 1.17–4.02, P = 0.0141).ConclusionsFactors predicting DI following TSS for NFPA were a younger age, larger tumor size, and the location of intrasellar HI on preoperative T1-weighted MRI.

PurposeThyrotropin-secreting pituitary adenomas (TSPA) are extremely rare pituitary adenomas; their perioperative thyroid hormone dynamics have not been completely elucidated. Here, we investigated the clinical characteristics, perioperative findings, and thyroid hormone dynamics of TSPA at a single institution.MethodsWe enrolled 11 patients who underwent transsphenoidal surgery (TSS) for TSPA during 2005–2019 at Hiroshima University Hospital (TSPA group) and 24 patients who underwent TSS for nonfunctioning pituitary adenomas (NFPA) in 2019 (NFPA group; for comparison). Their clinical characteristics, operative findings, and thyroid hormone dynamics, including serum thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4), were retrospectively analyzed.ResultsThe NFPA group demonstrated a slight temporary decrease in serum TSH/ FT3/ FT4 levels on day 1 postoperatively and improvement in the levels on day 4 postoperatively. In contrast, the serum TSH level in the TSPA group demonstrated a marked decrease on day 1 postoperatively but improved on day 7 postoperatively. The serum FT3 level was also markedly decreased on day 1 postoperatively but remained within the normal range. The serum FT4 level revealed a gradual decrease until day 21 postoperatively and then recovered within the normal range 3 months postoperatively. There was no significant difference in the frequency of decline in serum FT4 level between the two groups; no patients required thyroid hormonal replacement 3 months postoperatively.ConclusionsDespite a variable degree of transient hypothyroidism, all patients had a normal thyroid function after 3 months follow-up.

To share the experiences of organizing the epilepsy surgery program in Indonesia. This study was divided into two periods based on the presurgical evaluation method: the first period (1999–2004), when interictal electroencephalogram (EEG) and magnetic resonance imaging (MRI) were used mainly for confirmation, and the second period (2005–2017), when long-term non-invasive and invasive video-EEG was involved in the evaluation. Long-term outcomes were recorded up to December 2019 based on the Engel scale. All 65 surgical recruits in the first period possessed temporal lobe epilepsy (TLE), while 524 patients were treated in the second period. In the first period, 76.8%, 16.1%, and 7.1% of patients with TLE achieved Classes I, II, and III, respectively, and in the second period, 89.4%, 5.5%, and 4.9% achieved Classes I, II, and III, respectively, alongside Class IV, at 0.3%. The overall median survival times for patients with focal impaired awareness seizures (FIAS), focal to bilateral tonic–clonic seizures and generalized tonic–clonic seizures were 9, 11 and 11 years (95% CI: 8.170–9.830, 10.170–11.830, and 7.265–14.735), respectively, with p  = 0.04. The utilization of stringent and selective criteria to reserve surgeries is important for a successful epilepsy program with limited resources.

Wnts are secreted ligands that consist of 19 members in humans, regulate cell proliferation, differentiation, motility and fate in many stages including the embryonic stage and tumorigenesis. Wnts bind to cell surface receptors named Frizzleds and LRPs, and transduce their signals through β‐catenin‐dependent and ‐independent intracellular pathways. Gliomas are one of the most common intracranial tumors. Gliomas exhibit a progression associated with widespread infiltration into surrounding neuronal tissues. However, the molecular mechanisms that stimulate the invasion of glioma cells are not fully understood. We established two cell lines from human glioma cases and analyzed the expression of all Wnt and Frizzled members in these cell lines and other well‐known glioma cell lines by real‐time PCR study. The mRNA of Wnt‐5a and ‐7b and Frizzled‐2, ‐6 and ‐7 were overexpressed in glioma cells. The elevation of Wnt‐5a expression was most remarkable. Although Wnt‐5a is reported to have oncogenic and antioncogenic activity in several cancers, the role of Wnt‐5a signaling in human glioma cells remains unclear. Immunohistochemical study also revealed high expression of Wnt‐5a in 26 (79%) of 33 human glioma cases. The positivity of Wnt‐5a expression was correlated with the clinical grade. Knockdown of Wnt‐5a expression suppressed migration, invasion and expression of matrix metalloproteinase‐2 of glioma cells. Reciprocally, treatment with purified Wnt‐5a ligand resulted in stimulation of cell migration and invasion. MMP‐2 inhibitor suppressed the Wnt‐5a‐dependent invasion of U251 cells. These results suggested that Wnt‐5a is not only a prognostic factor but also a therapeutic target molecule in gliomas for preventing tumor cell infiltration. (Cancer Sci 2011; 102: 540–548)

Background Spontaneous intracranial hypotension (SIH) is secondary to a cerebrospinal fluid leak at the spinal level without obvious causative events. Several signs on brain and cervical spine magnetic resonance (MR) imaging (MRI) have been associated with SIH but can be equivocal or negative. This retrospective study sought to identify characteristic SIH signs on thoracic spinal MRI. Methods Cranial and spinal MR images of 27 consecutive patients with classic SIH symptoms, who eventually received epidural autologous blood patches (EBPs), were analyzed. Results The most prevalent findings on T2-weighted MRI at the thoracic level were anterior shift of the spinal cord (96.3%) and dorsal dura mater (81.5%), probably caused by dural sac shrinkage. These dural sac shrinkage signs (DSSS) were frequently accompanied by cerebrospinal fluid collection in the posterior epidural space (77.8%) and a prominent epidural venous plexus (77.8%). These findings disappeared in all six patients who underwent post-EBP spinal MRI. Dural enhancement and brain sagging were minimum or absent on the cranial MR images of seven patients, although DSSS were obvious in these seven patients. For 23 patients with SIH and 28 healthy volunteers, a diagnostic test using thoracic MRI was performed by 13 experts to validate the usefulness of DSSS. The median sensitivity, specificity, positive-predictive value, negative-predictive value, and accuracy of the DSSS were high (range, 0.913–0.931). Conclusions Detection of DSSS on thoracic MRI facilitates an SIH diagnosis without the use of invasive imaging modalities. The DSSS were positive even in patients in whom classic cranial MRI signs for SIH were equivocal or minimal.

The Hokkaido Eastern Iburi Earthquake (M = 6.7) occurred on Sep. 6, 2018 in the southern part of Central Hokkaido, Japan. Since Paleogene, this region has experienced the dextral oblique transpression between the Eurasia and North American (Okhotsk) Plates and the subsequent collision between the Northeast Japan Arc and the Kuril Arc due to the oblique subduction of the Pacific Plate. This earthquake occurred beneath the foreland fold-and-thrust belt of the Hidaka Collision zone developed by the collision process, and is characterized by its deep focal depth (~ 37 km) and complicated rupture process. The reanalyses of controlled source seismic data collected in the 1998–2000 Hokkaido Transect Project revealed the detailed structure beneath the fold-and-thrust belt, and its relationship with the aftershock activity of this earthquake. Our reflection processing using the CRS/MDRS stacking method imaged for the first time the lower crust and uppermost mantle structures of the Northeast Japan Arc underthrust beneath a thick (~ 5–10 km) sedimentary package of the fold-and-thrust belt. Based on the analysis of the refraction/wide-angle reflection data, the total thickness of this Northeast Japan Arc crust is only 16–22 km. The Moho is at depths of 26–28 km in the source region of the Hokkaido Eastern Iburi Earthquake. Our hypocenter determination using a 3D structure model shows that most of the aftershocks are distributed in a depth range of 7–45 km with steep geometry facing to the east. The seismic activity is quite low within the thick sediments of the fold–thrust belt, from which we find no indication on the relationship of this event with the shallow (< 10–15 km) and rather flat active faults developed in the fold-and-thrust belt. On the other hand, a number of aftershocks are distributed below the Moho. This high activity may be caused by the cold crust delaminated from the Kuril Arc side by the arc–arc collision, which prevents the thermal circulation and cools the forearc uppermost mantle to generate an environment more favorable for brittle fracture.

Background The G-protein-coupled receptor 40 (GPR40) is suggested to function as a transmembrane receptor for medium- to long-chain free fatty acids and is implicated to play a role in free fatty acids-mediated enhancement of glucose-stimulated insulin secretion from pancreas. However, the functional role of GPR40 in nervous system including somatosensory pain signaling has not been fully examined yet. Results Intrathecal injection of GPR40 agonist (MEDICA16 or GW9508) dose-dependently reduced ipsilateral mechanical allodynia in CFA and SNL models and thermal hyperalgesia in carrageenan model. These anti-allodynic and anti-hyperalgesic effects were almost completely reversed by a GPR40 antagonist, GW1100. Immunohistochemical analysis revealed that GPR40 is expressed in spinal dorsal horn and dorsal root ganglion neurons, and immunoblot analysis showed that carrageenan or CFA inflammation or spinal nerve injury resulted in increased expression of GPR40 in these areas. Patch-clamp recordings from spinal cord slices exhibited that bath-application of either MEDICA16 or GW9508 significantly decreased the frequency of spontaneous excitatory postsynaptic currents in the substantia gelatinosa neurons of the three pain models. Conclusions Our results indicate that GPR40 signaling pathway plays an important suppressive role in spinal nociceptive processing after inflammation or nerve injury, and that GPR40 agonists might serve as a new class of analgesics for treating inflammatory and neuropathic pain.

Approximately 26–30% of temporal lobe epilepsy (TLE) cases display a normal-appearing magnetic resonance image (MRI) leading to difficulty in determining the epileptogenic focus. This causes challenges in surgical management, especially in countries with limited resources. The medical records of 154 patients with normal-appearing MRI TLE who underwent epilepsy surgery between July 1999 and July 2019 in our epilepsy centre in Indonesia were examined. The primary outcome was the Engel classification of seizures. Anterior temporal lobectomy was performed in 85.1% of the 154 patients, followed by selective amygdalo-hippocampectomy and resection surgery. Of 82 patients (53.2%), Engel Class I result was reported in 69.5% and Class II in 25.6%. The median seizure-free period was 13 (95% CI,12.550–13.450) years, while the seizure-free rate at 5 and 12 years follow-up was 96.3% and 69.0%, respectively. Patients with a sensory aura had better seizure-free outcome 15 (11.575–18.425) years. Anterior temporal lobectomy and selective amygdala-hippocampectomy gave the same favourable outcome. Despite the challenges of surgical procedures for normal MRI TLE, our outcome has been favourable. This study suggests that epilepsy surgery in normal MRI TLE can be performed in centres with limited resources.